SUMMARY Pneumonia, caused by bacterial and/or viral etiology, is the leading cause of death in children worldwide. Preceding viral illness, linked to influenza infection, is a primary risk factor associated with secondary bacterial pneumonia. Influenza infection is an annual, seasonal cause of morbidity and mortality throughout the world. Severe influenza pneumonia is often exacerbated by bacterial infection resulting in poor patient outcomes in those with preexisting lung morbidity and in previously healthy individuals. The pandemic potential of influenza viruses heightens the importance of understanding disease pathogenesis. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence, while antibiotic resistance continues to propagate. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during pandemic outbreaks. During the previous funding period, our laboratory has identified suppression of bacterial-induced Type 17 immune responses by preceding influenza as a critical susceptibility mechanism. We have published extensively in the area of elucidating aberrant host defense pathways in this context. In this renewal application, we will build upon our ongoing work with three highly novel Aims derived from the original focus. We hypothesize that S. aureus-induced Type 17 innate immune activation is negatively regulated by influenza-induced STAT2 signaling and the Asc inflammasome. Further, we propose that exogenous antimicrobial peptide (AMP) therapy presents a novel therapeutic strategy in influenza, bacterial super-infection. In Aim 1 we will determine the mechanism(s) by which STAT2 signaling impairs anti-bacterial host defense against S. aureus during influenza super-infection. Aim 2 will focus on the mechanism(s) by which Asc inflammasome knockout mice are protected from exacerbation of secondary S. aureus infection. In Aim 3 we will investigate the mechanism of AMP production and evaluate the therapeutic potential of exogenous AMPs during influenza, S. aureus super- infection. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1), how the immune response to S. aureus is initiated in the lung (Aim 2), and test novel therapeutic approaches for controlling post-influenza secondary bacterial pneumonia (Aim 3). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super- infection and provide novel treatment targets in a pre-clinical model of disease.